ESSENTIAL MEDICINES LIST

FOR THE MANAGEMENT OF PATIENTS

ADMITTED TO INTENSIVE CARE UNITS
WITH SUSPECTED OR CONFIRMED
COVID-19 DIAGNOSIS

Update
10 August 2020
BACKGROUND

During the COVID-19 pandemic, many low-, medium-, and high-income countries have
depleted their reserves of the essential medicines required to manage patients with COVID-
19 in intensive care units (ICUs). Countries’ health emergency preparedness plans call for
the inclusion of a list of essential medicines and other medical devices that are required in
ICUs to confront health emergencies.

OBJECTIVES AND TARGET USERS OF THE LIST

The list of essential medicines for the management of patients admitted to ICUs with a
suspected or confirmed diagnosis of COVID-19 is a core guidance document that provides
assistance to countries’ health systems in prioritizing those essential medicines that should
be widely available and affordable for the management of patients in ICUs during health
emergencies––in this case, for patients with a suspected or confirmed diagnosis of COVID-
19.

This document is targeted to health officials and health system managers in the countries of
the Region of the Americas.

METHODS, CRITERIA USED TO DEVELOP THE LIST, AND INFORMATION SEARCH

STRATEGIES

This list basically includes the drugs that are considered indispensable for the management
of the array of clinical signs and symptoms most often seen in patients admitted to the ICU
as a result of SARS-CoV-2 infection.

The list does not include most of the drugs routinely kept in ICUs for the management of
other conditions or comorbidities, or to stabilize patients (e.g., insulin or antihypertensives),
except for those that may be needed to provide treatment or support (e.g., neuromuscular
blockers or anesthetics) for conditions triggered by the infection.

Also not included in the list are drugs used specifically to treat SARS-CoV-2 infection, since
no high-quality scientific evidence is available at present to support their use except in the
context of controlled clinical trials.

A team of experts on the subject searched for information on the care of ICU patients during
the COVID-19 pandemic using MEDLINE (through PubMed), Cochrane, Tripdatabase,
Epistemonikos, and global search engines on the internet (Google). Also included were
reviews and guidelines developed by the ministries of health of countries of the Region of
the Americas, the World Health Organization (WHO), the Pan American Health Organization
(PAHO), the National Institute of Health and Clinical Excellence (NICE) of the United
Kingdom, the Centers for Disease Control and Prevention (CDC) of the United States of
America, and the National Institutes of Health (NIH) of the United States.

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The following were some of the strategies and key words used to conduct the search:
("Intensive Care Units"[Mesh]) AND "Drugs, Essential"[Mesh], (Therapy/Broad[filter]) AND
(intensive care unit AND medicines AND COVID-19), (Therapy/Broad[filter]) AND (critically
ill patients AND COVID-19), (Therapy/Broad[filter]) AND (clinical management AND COVID-
19), (title:((title:(intensive care unit) OR abstract:(intensive care unit)) AND (title:(COVID-19)
OR abstract:(COVID-19))) OR abstract:((title:(intensive care unit) OR abstract:(intensive
care unit)) AND (title:(COVID-19) OR abstract:(COVID-19)))), (title:((title:(critically ill
patients) OR abstract:(critically ill patients)) AND (title:(COVID-19) OR abstract:(COVID-
19))) OR abstract:((title:(critically ill patients) OR abstract:(critically ill patients)) AND
(title:(COVID-19) OR abstract:(COVID-19))))

Evidence-based guidelines developed in accordance with the GRADE method were

identified and prioritized. Randomized controlled trials (RCTs), systematic reviews, and
meta-analyses were also identified, and any direct or indirect publication where the topic
was mentioned was also taken into account1-85.

For the research questions established, two reviewers selected the titles and abstracts
retrieved through the biomedical databases used. For each PICO (patient, problem, or
population; intervention; comparison; outcome) question, all studies that met the criteria
were examined.

The most important clinical presentations, symptoms and managements in critically ill
patients suffering from COVID-19 were identified, as prioritized in guidelines developed by
WHO3, 38, PAHO61, and the Surviving Sepsis Campaign (SSC)1.

Also considered were PAHO´s Guidelines for care of critically ill adult patients with COVID-
19 in the Americas: short version – v261; Clinical care for severe acute respiratory infection:
toolkit, adapted for COVID-19 in 2020 by WHO51; NICE´s Pneumonia (community
acquired): antimicrobial prescribing59; NICE´s COVID-19 rapid guideline: antibiotics for
pneumonia in adults in hospital64; and reviews on the management of critically ill patients
with COVID-1965, 66.

The list is grounded in the evidence-based management recommendations presented in the

above-mentioned guidelines, as well as systematic reviews and meta-analyses and the
WHO Model List of Essential Medicines.

The following clinical scenarios were selected:

1. Management of patients with hypoxemic respiratory failure and respiratory distress

syndrome.
2. Management of patients with hemodynamic compromise and septic shock.
3. Management of critically ill patients to prevent complications.

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The quality of the evidence and the strength of each recommendation were based on
analysis and on the recommendations in the prioritized guidelines1,38, as appropriate.

In SSC guidelines1, the GRADE method was used to assess the quality of the evidence,
which was classified as high, moderate, low, or very low. The recommendations are based
on the balance between benefits and risks, resources and costs, and on equity,
acceptability, and feasibility. The recommendations can be strong or conditional or take the
form of “best practices.” The guidelines use the phrase “we recommend” for strong
recommendations and “we suggest” for conditional or weak recommendations.

The WHO guideline development group38 did not follow a formal process based on GRADE.
The only time it makes a strong recommendation is when a declaration of good practice in
favor of a given intervention is involved. It also establishes recommendations against
interventions and makes conditional recommendations if special care is required in their
implementation.

Medicines were selected by applying the WHO method, namely, on the basis of efficacy,
safety, suitability, and cost criteria, with due consideration given to risk-benefit and cost-
suitability trade-offs.

The generic name or international nonproprietary name (INN) of the medicines was used,
and the inclusion of a single active ingredient was prioritized over fixed-dose combinations,
except in situations in which using these is justified, based on evidence pointing to lower
resistance or greater adherence to treatment. The active ingredients, their concentration,
and dosage forms are included. Recommended pharmaceutical presentations may vary by
country.

In the case of drugs with the same site and mechanism of action, the one costing less was
selected in most countries of the Region of the Americas in order to improve affordability. If
an option other than the proposed one is available in a given country at a lower cost, its use
may be considered. The list was organized and classified by therapeutic class. Priority was
given to including drugs and pharmaceutical forms contained in the 21st edition of the WHO
Model List of Essential Medicines, published in 2019.

This list will be updated as new evidence becomes available.

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SCIENTIFIC BASIS FOR KEY DRUGS IN THIS LIST. EVIDENCE LEVEL AND
STRENGTH OF THE RECOMMENDATION

Drugs used specifically for the treatment of SARS-CoV-2 infection

More than 1,000 randomized trials involving drugs for the treatment of patients with COVID-
19 are currently registered81.

The Solidarity and Recovery trials have suspended the use of hydroxychloroquine and of
lopinavir and ritonavir in patients hospitalized with this disease in view of the lack of benefit
in reducing mortality in these patients78-80, 85.

Preliminary data from the Adaptive COVID-19 Treatment Trial (ACTT)72 suggest that in
patients treated with remdesivir, time to recovery was a statistically significant four days
faster, on average, than in patients who received placebo. However, the difference in
mortality rates was not statistically significant72, 73.

The rapid review conducted by PAHO74 before this list was updated presents a meta-
analysis of two randomized clinical trials, and the significant benefit in terms of mortality
varies in accordance with the statistical method used. The certainty of the evidence was
regarded as moderate primarily because of imprecision (small number of events, small
sample, wide confidence intervals) and inconsistency (high I2)74.

Some low-quality studies suggest that tocilizumab can significantly reduce the risk of
invasive mechanical ventilation or death in patients with severe pneumonia from COVID-
1976-77. In the last review conducted by PAHO74, which included meta-analysis of the
available data, no benefits deriving from the use of tocilizumab are indicated. The panel of
experts for NIH guidelines43 regards the available data as still not sufficient to issue a
recommendation for or against the use of interleukin-6 inhibitors (such as tocilizumab) for
the management of COVID-19.
As a result, these medicines are not included in the current list, given the lack of high-
quality evidence in favor of using them at the time of this update.

1. Management of patients with hypoxemic respiratory failure and respiratory

distress syndrome

Drugs for the management of sedation, analgesia, delirium, and muscle

relaxation in critically ill patients on mechanical ventilation in the intensive care
unit

Sedation, analgesia, delirium management, and muscle relaxation are integral parts of the
management of critically ill patients in ICUs and are particularly important in patients on
mechanical ventilation. A large number of patients with COVID-19 will need mechanical

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ventilation because of respiratory failure. An expert panel has recently recommended that
patients diagnosed with coronavirus infection be managed the same way as any other
patient on mechanical ventilation1.

The first clinical practice guidelines recommended (with a low level of evidence) the use of
diazepam or midazolam for rapid sedation in agitated patients; of lorazepam for the
management of most patients requiring sedation; and of propofol as the preferred sedative
when rapid awakening is required (neurological assessment or patient who will be
extubated). Similarly, they recommended haloperidol as the drug of choice in the treatment
of delirium, a condition that is frequent among critical care patients29.

Benzodiazepines and haloperidol have been and continue to be, in many ICUs, the drugs
most often used when sedation or treatment for delirium are required, respectively.
However, more recent clinical practice guidelines suggest the use of propofol or
dexmedetomidine over that of benzodiazepines for managing sedation in critically ill adults
on mechanical ventilation30-31, and they suggest not using haloperidol or atypical
antipsychotics routinely for the treatment of delirium, with the clarification that both classes
of antipsychotics can be used for short periods in selected patients. Dexmedetomidine is not
among the medicines included in the WHO Model List of Essential Medicines for 2019. For
this reason, consideration was given to including the other therapeutic options, despite
limited evidence.

The use of neuromuscular relaxants in patients on mechanical ventilation is associated with

improved oxygenation, prevents ventilator dyssynchrony, and reduces airway pressures,
potential pulmonary lesions and barotrauma. Different guidelines agree on the need to use
neuromuscular blocking agents in the management of adult patients with acute respiratory
distress syndrome (ARDS)1,32. In adults with COVID-19 and mild to moderate ARDS, the
most recent guidelines suggest using boluses of muscle relaxants on demand instead of
continuous infusion and suggest reserving intravenous (IV) infusion, lasting no more than
48 hours, for the following cases: patients with persistent ventilator dyssynchrony; patients
requiring very deep sedation; patients being ventilated in the prone position; and patients
with a persistently high plateau pressure in the airways1. The most important clinical trial
underpinning the recommendations was conducted with cisatracurium33. Atracurium is a
muscle relaxant closely resembling cisatracurium structurally and with similar
pharmacodynamic and pharmacokinetic properties, but less costly. Both cisatracurium and
atracurium are metabolized through plasma mechanisms independent of the liver and their
clearance is not affected by renal function. Vecuronium, which is considered an alternative
option, can undergo more pharmacokinetic alterations in patients with impaired liver and
kidney function34. Since they are currently options, given their inclusion in the WHO Model
List of Essential Medicines, atracurium and vecuronium will be included.

Succinylcholine, a short-acting depolarizing relaxant, is reserved for cases requiring

emergency orotracheal intubation in the ICU35.

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Opioids continue to be a cornerstone of pain management and sedoanalgesia in patients on
mechanical ventilation. The opioids that are most highly rated and most often recommended
in clinical practice guidelines for the management of critically ill patients are morphine and
fentanyl1, 29, 30.

On the basis of the aforementioned evidence, a list of essential medicines for the
management of sedation, analgesia, delirium, and muscle relaxation in critically ill
patients in the ICU should include the following: under benzodiazepine sedatives,
midazolam and lorazepam; under non-benzodiazepine sedatives, propofol; under
antipsychotics, haloperidol; under neuromuscular relaxants, succinylcholine,
atracurium, or vecuronium; under opioids, morphine and fentanyl.

It is important to note that Surviving Sepsis Campaign1 guidelines suggest using, as

necessary, intermittent boluses of neuromuscular blocking agents instead of
continuous infusion to facilitate lung-protective ventilation (evidence of low quality,
weak recommendation).

Use of corticosteroids. Acute respiratory distress syndrome (ARDS-COVID-19).

a- In adult patients with COVID-19

No data are available on the use of corticosteroids in patients with COVID-19 and shock.
However, indirect evidence from critically ill patients in shock, based on comparisons of low-
dose corticosteroid therapy versus no corticosteroid therapy, showed no significant
differences in short-term mortality (relative risk [RR]: 0.96; 95% confidence interval [CI]:
0.91–1.02) or long-term mortality (RR: 0.96; 95% CI: 0.90–1.02), although the time to shock
resolution and hospital stay were shorter when corticosteroids were administered21-23.

In a multicentric randomized controlled trial conducted in 17 ICUs in Spain in patients with

moderate to severe ARDS, early administration of dexamethasone was shown to
reduce the duration of mechanical ventilation and overall mortality36.

In March 2020, a systematic review67 on the use of systemic corticosteroids in this type of
patients was published. It included a meta-analysis of the results of the last 2019 Cochrane
review23 and those of the aforementioned multicentric clinical trial36. The results obtained
suggest that systemic corticosteroids may improve mortality, duration of mechanical
ventilation, and number of days without mechanical ventilation. On the other hand,
hyperglycemia was observed, along with an unclear effect on muscle weakness.

A PAHO systematic review looked at the efficacy and safety of the use of corticosteroids; it
included meta-analysis of 8 RCTs in patients with COVID-19 and ARDS. Results showed a
decrease in mortality among patients who received corticosteroids (RR: 0.74; 95% CI: 0.63–
0.86; 1858 patients). In subgroup analyses, the effect remained robust among patients who
received dexamethasone (RR: 0.70; 95% CI: 0.59–0.83; 1284 patients), but not among
those who received hydrocortisone or budesonide. According to another meta-analysis of 8
observational studies with 1898 patients, no differences in adverse events were noted

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between patients treated with corticosteroids and those who received no steroids (RR: 2.08;
95% CI: 0.97–4.46), I2: 85%). The quality of the evidence is low due to the risk of bias and
imprecision61.
Another systematic review and meta-analysis reported that in patients with COVID-19 and
ARDS, corticosteroids may significantly reduce mortality (one cohort study with 84 patients;
hazards ratio [HR] = 0.41; 95% CI: 0.20–0.83; evidence of very low quality). This reduction
was also seen in patients with ARDS without COVID-19 (7 RCTs with 851 patients; RR =
0.72; 95% CI: 0.55–0.93; low-quality evidence). In patients with severe COVID-19 but
without ARDS, direct evidence from two observational studies showed an increase in
mortality with the use of corticosteroids (HR = 2.30; 95% CI: 1.00–5.29), but the evidence
was of very low quality. Randomized controlled trials on community-acquired pneumonia
suggest that corticosteroids may reduce mortality (RR = 0.70; 95% CI: 0.50–0.98; evidence
of very low quality) and increase hyperglycemia. Overall, the quality of the evidence is low
or very low owing to imprecision, inconsistency, and indirectness82.
A systematic review of 23 studies (including one RCT and 22 cohort studies), with a total of
13 815 patients, found that in adults with COVID-19, the use of systemic glucocorticoids did
not reduce mortality (RR = 2.00; 95% CI: 0.69–5.75; I2 = 90.9%) or the duration of lung
inflammation (mean weighted difference [MWD] = -1 day; 95% CI: -2.91 to 0.91], but a
significant reduction in the duration of fever was noted (MWD = -3.23 days; 95% CI: -3.56
to -2.90). In patients with SARS, glucocorticoids did not reduce mortality (RR = 1.52; 95%
CI: 0.89–2.60; I2 = 84.6%), the duration of fever (MWD = 0.82 days; 95% CI: -2.88 to 4.52;
I2 = 97.9%) or the time to absorption of lung inflammation (MWD = 0.95 days; 95% CI: -7.57
to 9.48; I2 = 94.6%) either. The use of systemic glucocorticoid therapy prolonged hospital
stay in all patients (COVID-19, SARS, and Middle East respiratory syndrome [MERS])83.
More recently, the published results of the Recovery RCT showed that in patients
hospitalized with COVID-19, dexamethasone significantly reduced mortality at 28 days in
those who required invasive mechanical ventilation (RR = 0.64; 95% CI: 0.51–0.81;
p<0.001) or oxygen (RR = 0.82; 95% CI: 0.72–0.94; p = 0.002). No benefit was seen in
patients who did not require assisted ventilation (RR = 1.19; 95% CI: 0.91–1.55; p = 0.14)68-
69, 84. On the basis of these results, one death would be prevented by treating approximately

eight ventilated patients or 34 patients requiring oxygen only.

Dexamethasone is a drug that has been included in the WHO Model List of Essential
Medicines in multiple forms since 1977. It is currently off patent and available at an
affordable price in most countries70.

The most recent SSC guidelines1 recommend the use of systemic glucocorticoids only in
patients who have respiratory failure with ARDS.

In adult patients with COVID-19 and in shock who require the addition of a second
vasopressor, administering a low dose of corticosteroids is suggested. This is a
conditional recommendation based on evidence of low quality61.

PAHO´s most recent Guidelines for care of critically ill adult patients with COVID-19 in the
Americas recommend administering corticosteroids at low doses to critically ill

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patients who are on supplementary oxygen or on a ventilator, in order to reduce
mortality and progression to invasive mechanical ventilation (strong recommendation
based on evidence of moderate quality) 61.

Given these results and recommendations, the critical importance of restricting volume in
this type of patients, and the fact that other corticosteroids were already included in the first
edition of this list, the current updated version includes dexamethasone instead of
methylprednisolone for the treatment of critically ill patients with COVID-19 who require
supplementary oxygen or assisted ventilation, and hydrocortisone for the treatment of
patients with COVID-19 and refractory septic shock43.

In adult patients with COVID-19

Routine use of corticosteroids is not recommended for the treatment of viral

pneumonia38,6 in adults unless indicated for another reason, such as exacerbations
of asthma or of chronic obstructive pulmonary disease (COPD), septic shock or
ARDS. A benefit-risk analysis should be conducted for each patient.

The use of systemic glucocorticoids is only recommended in patients who have

respiratory failure with ARDS1.

Administering corticosteroids at low doses to critically ill patients who are on

supplementary oxygen or on a ventilator is recommended to reduce mortality and
progression to invasive mechanical ventilation (strong recommendation based on
evidence of moderate quality)61.

b- In children
To date, no high-quality studies are available in support of or against the routine use of
adjuvant glucocorticoids to treat pediatric septic shock or another organic dysfunction
associated with sepsis. One clinical trial is currently being developed to look at the potential
risks and benefits of adjuvant hydrocortisone for treating septic shock that is refractory to
fluid therapy and to vasoactive-inotropic agents in children.

Hydrocortisone can be prescribed at stress doses, with or without assessment of the

adrenal axis2,37, only in situations in which a child with septic shock or another form
of sepsis associated with organic dysfunction is known to have suffered acute or
chronic exposure to corticosteroids; disorders of the hypothalamic-pituitary-adrenal
axis, congenital adrenal hyperplasia, or other endocrinopathies related to
corticosteroids; or to have recently been treated with ketoconazole or etomidate.

In children with COVID-19

In the case of septic shock or other organic dysfunction, no good quality evidence is
available that either supports or refutes the use of corticosteroids.

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They should be used only if the child has previously suffered acute or chronic
exposure to corticosteroids; disorders of the hypothalamic-pituitary-adrenal axis,
congenital adrenal hyperplasia, or another endocrinopathy related to corticosteroids;
or has recently been treated with ketoconazole or etomidate. In such cases,
hydrocortisone can be prescribed at stress doses, with or without assessment of the
adrenal axis2.

Hydrocortisone is being conditionally included in this list, pending further evidence.

2. Management of patients with hemodynamic compromise and septic shock

The prevalence of shock in adult patients with COVID-19 varies considerably (from 1% to
35%). In hospitalized patients, its incidence can be as high as 20-35%6, which explains the
need to identify the best therapeutic options for its treatment.

Parenteral solutions

Cardiac dysfunction is common in patients with COVID-19 (7% to 23%)7-10. Fluid

management in critically ill patients with COVID-19 admitted to ICUs (with or without septic
shock) is a key, clinically significant element, both in terms of the quantity and the type of
fluids that should be used in these cases.

The indirect evidence obtained on hemodynamic and fluid replacement management in

critically ill patients included in 13 RCTs shows that appropriate fluid therapy can reduce
mortality (RR = 0.59; 95% CI; 0.42–0.83) and hospital stay among critically ill patients in the
ICU11 (mean difference [MD] = -1.16 days; 95% CI: -1.97 to -0.36).

Appropriate fluid management has as much to do with the quantity as with the type of fluid
administered. As concerns the first point (the amount of fluid that should be used in critically
ill patients), the comparison between restricting fluids and administering fluids freely in
patients with septic shock is arguably inconclusive with respect to mortality (RR = 0.87; 95%
CI: 0.69–1.10) and serious adverse events (RR = 0.91; 95% CI: 0.78–1.05)12. However, all
the results examined appear to favor conservative and restrictive fluid therapy with
administration of low fluid volumes13,38, and the avoidance of large fluid volumes, even in
pediatric patients14.

In conclusion, the recommendation concerning the volume of fluids that should be

used in critically ill patients favors restrictive use. This recommendation is
conditional and is based on evidence of low quality1.

In reference to the type of fluids that should be used (crystalloids or colloids), there is one
systematic review of 69 RCTs (n = 30 020 patients) in which16 both types of fluids were
compared in critically ill patients with COVID-19 and shock16; statistically significant
differences in mortality were not found (RR = 0.97; 95% CI: 0.86–1.09) at 1 and 3 months.

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However, the risk of kidney damage and the need for transfusion are higher with colloids
(RR = 1.30; 95% CI: 1.14–1.48)16. By crystalloids we mean normal saline solution and
Ringer´s lactate solution.

Considering that certain colloids are harmful, more expensive than crystalloids, and have
limited availability in certain contexts (low- and middle-income countries), the SSC guideline1
development panel recommends using crystalloid solutions as fluids to resuscitate patients
with COVID-19 and shock.

In conclusion, the recommendation concerning the use of crystalloids versus

colloids in critically ill patients with COVID-19 favors the use of crystalloids. This
recommendation is strong and is based on evidence of moderate quality1.

A breakdown of the data by type of colloid used in these comparative studies with
crystalloids shows the following:

The use of albumin as a colloidal plasma volume expander in critically ill patients was
addressed in 20 RCTs involving 13 047 patients. Trial results showed no benefits associated
with albumin administration (weak recommendation, evidence of moderate quality)16.

Additionally, no studies are available on the use of gelatins in patients with COVID-19.
Indirect evidence from one systematic review of six RCTs involving 1,698 patients who were
critically ill from other causes and in which the colloid given was a gelatin showed no
mortality benefit at days 30 and 90, with disadvantages in terms of costs versus benefits.
For this reason, the use of gelatins is not recommended (conditional recommendation,
evidence of low quality)16.

Nineteen RCTs with 4,736 enrolled patients compared using crystalloids with using a colloid
such as dextran. No benefits favoring the latter were reported, whereas a disadvantage
noted was an increase in red blood cell transfusion requirements (weak recommendation,
evidence of low quality)16.

More than 11,000 patients enrolled in 24 RCTs in which hydroxyethyl starch was used as
the colloid in the comparison with crystalloids. The trials showed that, despite the lack of
differences in mortality, starches pose a greater risk of needing red blood cell transfusions
and renal replacement therapy than crystalloids (strong recommendation, evidence of
moderate quality)16.

The use of colloidal plasma expanders such as albumin, gelatins, dextran, or starches
has shown lower cost-effectiveness than the use of crystalloids. This
recommendation is conditional, and the quality of the evidence is low or moderate
(an exception is starch, whose recommendation is strong and based on evidence of
moderate quality)1, 16.

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The use of crystalloids for critically ill adult patients with COVID-19 is therefore
recommended.

To determine what type of crystalloids are most beneficial for replacing or expanding volume
(balanced crystalloid solutions versus 0.9% saline solution) 1 when resuscitating critically ill
patients, a Cochrane systematic review was conducted in 2019. It failed to show significant
differences between treatments in terms of mortality (odds ratio [OR] = 0.91; 95% CI: 0.83–
1.01) or acute renal injury (OR = 0.92; 95% CI: 0.84–1.00)15. However, the data did suggest
a potential benefit of balanced crystalloid solutions for resuscitating patients with COVID-19
and shock.

One final systematic review with meta-analysis39 found that in critically ill adult patients,
although not specifically those with sepsis, mortality was lower at days 28-30 among those
resuscitated with balanced crystalloid solutions than among those resuscitated with saline
solution.

The SCC guidelines suggest that the use of buffered balanced crystalloids is superior to the
use of unbalanced crystalloids. This evidence is of moderate quality, and the
recommendation is conditional.

In conclusion, balanced crystalloid solutions such as Ringer´s lactate or, if

unavailable, 0.9% sodium chloride solutions are recommended, with restrictive
administration, to replace fluids in critically ill patients with COVID-19. Hypotonic
solutions are not to be used. This is a conditional recommendation based on evidence
of moderate quality1.

In light of the limited availability of balanced crystalloid solutions 1, 0.9% sodium chloride
solution continues to be a reasonable alternative.

Although in critically ill patients with COVID-19 recommendations are to use fluids sparingly,
choose crystalloids and, within this category, balanced crystalloid solutions such as Ringer´s
lactate, the mode and rate of administration of these fluids must be determined in
accordance with the type of patient being treated38.

1 Crystalloid solutions are defined as those containing water, electrolytes, and/or sugars in different proportions
and osmolarities. With respect to plasma, they can be hypotonic, hypertonic, or isotonic. These solutions
include 0.9% sodium chloride hydrosaline (sodium 154 mEq / osmolarity 308 mOsm/L), Ringer’s (148 mEq
sodium / osmolarity 310 mOsm/L), Ringer’s lactate (sodium 130 mEq / lactate 28 mEq / osmolarity 272
mOsm/L), 5% dextrose in saline solution (glucose 50 g/ sodium 154 mEq / osmolarity 560 mOsm/L), and 5%
dextrose in water (glucose 50 g / osmolarity 253 mOsm/L). Colloidal solutions such as dextran are plasma
expanders containing high-molecular-weight particles in suspension that do not cross capillary membranes.
Thus, they are capable of increasing plasma osmotic pressure and of retaining water in the intravascular
space. Human albumin has also been used as a plasma expander at 5% or 25% in isotonic solution.
Administration of albumin 25% solution increases intravascular volume by five times the albumin volume
administered over 30 to 60 minutes.

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Thus, in adult patients administering 250-500 ml of crystalloid fluid as a bolus over the first
15-30 minutes of resuscitation efforts for septic shock is recommended.38

In resuscitation for septic shock in children, administering 10-20 mL/kg of crystalloid fluid
as a bolus over the first 30-60 minutes is recommended.38

Additional boluses may be needed (250-500 ml in adults; 10-20 ml/kg in children) depending
on the clinical response and on improvements with respect to perfusion objectives;
continuous vigilance for possible signs of fluid overload after each bolus is required.
Perfusion objectives include achieving a mean arterial pressure >65 mmHg in adults, or an
appropriate equivalent pressure depending on the age of the affected children; a urine
output >0.5 ml/kg/h in adults or >1 ml/kg/ h in children; and improved skin and limb perfusion,
heart rate, and level of consciousness14, 38, 40.

Vasoactive drugs

Given the absence of direct evidence in patients with COVID-19 and shock, indirect
evidence from critically ill patients in general can guide the therapeutic decision-making
process in these cases.

In adults with COVID-19 and shock, norepinephrine is recommended as first choice (a

comparison of norepinephrine with vasopressin or epinephrine in this type of patient showed
no significant differences in mortality, although epinephrine was associated with more
pronounced tachycardia and excess lactate production1,17). If norepinephrine is not
available, vasopressin or adrenaline should be used as first choice.1

In adults with COVID-19 and shock who show signs of cardiac dysfunction and persistent
hypoperfusion despite resuscitation with fluids and norepinephrine, the recommendation is
to add dobutamine1, 18, 19, 20 without first attempting to increase the dose of norepinephrine.

For children with COVID-19 and septic shock who have organ dysfunction, SSC guidelines2
recommend both epinephrine and norepinephrine, which were assessed in comparison with
dopamine. But since clinical trials comparing the two drugs with each other are not available,
it is suggested that the decision to select one or the other as first choice be based on the
patient’s pathophysiological condition (preference for epinephrine to treat myocardial
dysfunction and low cardiac output, and for norepinephrine to increase vascular resistance)
and on local factors.

In light of the above, it is recommended to start with norepinephrine in critically ill

patients with COVID-19 and cardiogenic or septic shock who require hemodynamic
support. If norepinephrine is not available, vasopressin or adrenaline may be used.
According to the most recent WHO guidelines38, the recommendation in favor of this
intervention is strong.

If there is evidence of cardiac dysfunction or persistent hypoperfusion, dobutamine

may be used. This is a conditional recommendation, since it calls for special care38.

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In children, epinephrine is considered the first line of treatment, while norepinephrine
is administered if shock persists despite an optimal dose of epinephrine2.

On the basis of the evidence presented, this list includes dobutamine, vasopressin,
and norepinephrine, despite their not being included in the 21st edition of the 2019
WHO Model List of Essential Medicines50.

Management of septic shock. Use of antimicrobials

See the description in the following section.

3- Management of critically ill patients. Drugs to prevent complications

Antipyretic treatment
According to the findings of a population-based cohort study conducted in hospitalized
patients with COVID-19, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was
associated with a significant increase in all-cause mortality, admissions to ICUs, the need
for mechanical ventilation, and/or sepsis (primary composite variable analyzed, OR = 1.54;
95% CI: 1.13–2.11). No significant increase in cardiovascular or renal complications was
observed (secondary variable, cardiovascular complications: OR = 1.54; 95% CI: 0.96–2.48,
or acute renal failure OR = 1.45; 95% CI: 0.49–4.14). The conclusion stemming from the
findings of this study is that NSAIDs should be used with caution in hospitalized patients
with COVID-19, since the harms associated with their use can outweigh the benefits in this
population71.

In view of the evidence available to date and the aforementioned data, and on the basis of
the precautionary principle, this list includes paracetamol, rather than an NSAID, as an
antipyretic.

Antimicrobial treatment

The prevalence of coinfections, or concomitant secondary infections, in cases of COVID-19

has not been precisely determined yet, although it appears to be low and to depend on local
and endemic factors38, 75.

Symptoms of secondary bacterial infection in patients with COVID-19 can be similar to those
of the underlying viral infection, which hinders its diagnosis. This is indirectly reflected in the
high rates of administration of IV antimicrobials in Wuhan: 53% of non-severe cases and
>90% of patients who were hospitalized or in the ICU1, 7-8.

With respect to patients with COVID-19 who experience a secondary bacterial infection, a
recent systematic review of hospitalized patients with COVID-19 found that only 8% were
reported to have a bacterial or fungal coinfection while in the hospital8.

13
As a result, recommendations are based on data extrapolated from other viral pneumonias
with potential for bacterial superinfection, on evidence-based guidelines26 and
recommendations, and on other clinical scenarios involving this type of infection (viral
pneumonias resulting from influenza1, pneumonias associated with mechanical ventilation3,
sepsis).

In the presence of acute coinfections, empirical antimicrobial therapy in critically ill adults
with COVID-19 who are in an ICU should be based on the clinical diagnosis, time elapsed
since admission of the patient to the hospital, diagnosis of sepsis, and local epidemiological
data on sensitivity to antimicrobials (community-acquired pneumonia, healthcare-associated
pneumonia).

In light of these considerations, recommendations concerning the use of antimicrobials in

critically ill patients with COVID-19 with suspected bacterial superinfection concomitant with
this viral infection are as follows:

On the initiation of empirical antibiotic therapy:

 In patients with suspicion or diagnostic confirmation of mild COVID-19, the

recommendation is NOT TO USE antibiotic therapy or prophylaxis (strong
recommendation against its use)38.

 In patients with suspicion or diagnostic confirmation of moderate COVID-19, the

recommendation is not to use antimicrobial therapy unless bacterial infection is
clinically suspected.

 In patients with suspicion or diagnostic confirmation of COVID-19 presenting

clinically as severe COVID-19, the recommendation is to begin with early empirical
use of antimicrobial agents to treat the probable pathogens, with reliance on clinical
judgment, host-related factors, and local epidemiological trends (strong
recommendation in favor of the intervention)38.

On timing and timeliness in the use of antimicrobials and treatment length in seriously ill
patients:

 With regard to the timing and timeliness with which antimicrobials should be
administered to critically ill patients with COVID-19 and sepsis, empirical
antimicrobials should be administered to treat the responsible pathogens within the
first hour after they are diagnosed3,5. In general, the length of treatment with
antimicrobials must be as short as possible, depending on clinical course: 5 to 7
days.

On the type of antimicrobial that should be used:

 In general, the majority of patients with severe sepsis and septic shock have some
level of immunocompromise, which is grounds for considering initiating treatment
with a broad-spectrum antimicrobial class such as carbapenems (e.g., meropenem,

14
 imipenem/cilastatin) or a combination of broad-spectrum penicillins or ß-lactamase
inhibitors (e.g., piperacillin/tazobactam). Third-generation (ceftriaxone) or fourth-
generation cephalosporins may also be used, especially as part of a combination
therapy regimen26.

 Some patients may have risk factors leading to suspicion of invasive infections with
Candida spp. 2 If the risk of sepsis from Candida spp. justifies empirical antifungal
therapy, the choice of the specific agent should be in keeping with the severity of the
disease, local patterns for the most common Candida species, and any recent
exposure to antifungal agents. Empirical use of amphotericin B is a reasonable
recommendation in these patients26.

 On the other hand, in pediatric patients with COVID-19, an estimated 20% has
coinfection with Mycoplasma pneumoniae, and although this percentage has not
been clearly established yet27, in this population as well as in adults a combination
of a ß-lactam antibiotic such as ampicillin plus a macrolide has been used in
community-based patients.

On the route of administration:

 For COVID-19 patients with severe pneumonia, antimicrobial therapy is

administered intravenously51.

Considerations concerning the treatment of severe pneumonia:

When a patient seeks medical care for suspected pneumonia, pneumonia from COVID-19
and bacterial pneumonia are difficult to tell apart on the basis of clinical features alone64.

During the COVID-19 pandemic to date, most pneumonias have been viral. The evidence
thus far suggests that bacterial coinfection occurs in fewer than 10% of patients with COVID-
19. Nonetheless, patients in critical care are at higher risk of bacterial infection than patients
in other hospital wards or settings64.

From the data furnished by the experience of countries where the pandemic began at an
earlier date, it can be concluded that, to a greater or lesser extent, up to 20% of the pediatric
population and of adults may have coinfection with Mycoplasma pneumoniae. For this
reason, it becomes necessary to include a macrolide in the therapeutic armamentarium for
use in this scenario27, 52.

In compliance with the WHO recommendation and the prioritized evidence-based

guidelines26, 38, 51, 61, 64, included in this list are antimicrobials for the empirical treatment of
patients with severe pneumonia. Empirical treatment should be based on the clinical
diagnosis (community-acquired pneumonia, hospital-acquired pneumonia), local

2 These factors include immunocompromised states (neutropenia, chemotherapy, transplant, diabetes mellitus,
chronic liver failure, chronic renal failure), long-term invasive vascular devices (hemodialysis catheters, central
venous catheters), total parenteral nutrition, necrotizing pancreatitis, recent surgery (particularly abdominal),
prolonged administration of broad-spectrum antimicrobials, prolonged admission to hospital/ICU, colonization.

15
epidemiological trends, and local bacterial susceptibility. Antibiotics having the lowest
ecological impact should be selected in accordance with data and guidelines from one´s
own institution, country, or region (choosing antibiotics from the ACCESS group in the WHO
categorization is recommended)38.

In cases of suspected community-acquired bacterial pneumonia, a combination of a ß-

lactam antibiotic (ampicillin, amoxicillin-clavulanic acid) and a macrolide (clarithromycin), or
of a cephalosporin such as ceftriaxone and a macrolide, are the recommended treatments
from among the therapeutic options included.

As an alternative to the use of macrolides, some guidelines suggest using doxycycline (to
be avoided during pregnancy) or levofloxacin51, 64 (which are not included in this list because
they offered no additional benefit).

The use of macrolides may be associated with a prolonged QT interval and can intensify the
effect of other drugs that might be used to treat infection with SARS-CoV-2. This was seen
among patients with COVID-19 who were treated with azithromycin and hydroxychloroquine,
since the group that received azithromycin had a longer QT interval (23 [10 to 40]
milliseconds) than patients who received hydroxychloroquine only (5.5 [-15.5 to 34.25]
milliseconds; p = 0.03)62.

Chorin et al.63 reported in a prepublication distributed by medRxiv that with the use of
hydroxychloroquine plus azithromycin, 30% of the patients showed a prolonged QTinterval,
potentially in excess of 500 milliseconds in 11% of cases. It is worth noting that this is a non-
peer-reviewed publication and that the study provides no other data that would indicate, for
instance, whether patients’ plasma levels of K+ were known63.

Furthermore, of the clinical trials for COVID-19 that have been published to document the
characteristics of patients admitted to the hospital for this disease and the prevalence of
comorbidities and complications, among other things, very few mention the rate of
occurrence of arrhythmias. According to a study from China, published in early February,
involving 138 patients infected with the coronavirus who were hospitalized with pneumonia,
16.7% of them suffered arrhythmia as a complication, and 44.4% of these were in the ICU8.

The WHO Model List of Essential Medicines50 includes clarithromycin, in the macrolide class
of drugs, for the treatment of severe pneumonia in adults and children over 5 when coverage
for atypical microorganisms is considered necessary. It does not include azithromycin for
this indication pursuant to a review by the expert committee that updated the WHO Model
List of Essential Medicines for the year 201753, which determined that:

1. analysis of a Cochrane systematic review in patients with community-acquired

pneumonia54 revealed a significantly higher rate of adverse effects with azithromycin
than with levofloxacin, and a significantly higher rate of adverse effects with
erythromycin than with clarithromycin, but no data was reported for the comparison
between clarithromycin and levofloxacin54.

16
 2. the Food and Drug Administration (FDA) of the United States issued a warning about
fatal cardiovascular events (arrhythmias) with azithromycin55.

It is important to note that in 2018, the FDA56 also issued an alert on the use of clarithromycin
in patients with heart disease, based on data from the CLARICOR clinical trial57-58.

NICE guidelines on community-acquired pneumonia and the prescription of antimicrobials59

make reference to the fact that the developing committee discussed the evidence on the
effectiveness of azithromycin. However, it determined that because of its long half-life and
the resulting greater likelihood of resistance, this drug was a less desirable option than other
macrolides and made the decision not to include it among its recommendations.

With due regard to the recommendations and evidence previously presented, priority is
given to the use of clarithromycin. This is because, owing to its shorter half-life, it would
allow for better management in the treatment of severe pneumonia in cases of severe
COVID-19 only when antimicrobial therapy for atypical microorganisms is considered
necessary. EKG monitoring of the QT interval while using this drug is recommended.

Furthermore, since local circulation of seasonal influenza is continuous, neuraminidase

inhibitor therapy should be considered for the treatment of flu patients who are at risk of
becoming gravely ill from COVID-193,60.

For this reason, and considering that antimicrobial susceptibility patterns vary
locally, it is recommended that the following antimicrobials be included in the list
of medicines for the treatment of complications from superinfection in critically ill
patients with COVID-19: amikacin, amoxicillin-clavulanate/ampicillin-sulbactam,
clarithromycin, amphotericin B, ceftazidime, ceftriaxone, meropenem/imipenem-
cilastatin, piperacillin-tazobactam, vancomycin, and oseltamivir26,28.

Prevention of thromboembolism

Coagulopathy is common among patients with severe COVID-19 and with venous and
arterial thromboembolism38. It has been associated with inflammation and a prothrombotic
state, with increased fibrin, fibrin degradation products, fibrinogen and D-dimer41-43. These
markers have been associated with less favorable clinical outcomes43-45.
The incidence of these complications as a function of disease severity has not been
completely determined. Among patients in the ICU, the incidence of thromboembolic
disease associated with COVID-19 appears to be higher43, 46-47.
In a prospective, multicentric French cohort study of 150 patients in the ICU, 16.7%
developed pulmonary embolism despite prophylactic anticoagulation. Patients with COVID-
19 and ARDS had a higher incidence of pulmonary embolism in comparison with patients
who did not have ARDS in association with COVID-1947. A Dutch study of 184 patients in
the ICU reported a cumulative incidence of venous thromboembolism of 27% (95% CI: 17%–
32%), despite prophylaxis48.

17
A study using routine ultrasound reported an incidence of venous thromboembolism of 69%
among patients admitted to the ICU46.

Pharmacological prophylaxis with low-molecular-weight heparin (such as

enoxaparin)61 is recommended, when not contraindicated, in hospitalized patients
(adults and adolescents) with COVID-19 to prevent venous thromboembolism. For
those who have contraindications, mechanical prophylaxis (intermittent pneumatic
compression devices) is recommended. According to WHO guidelines38, the
recommendation in favor of this intervention is strong.
This guideline also recommends monitoring patients with COVID-19 for signs or
symptoms suggestive of thromboembolism, such as stroke, deep vein thrombosis,
pulmonary embolism, or acute coronary syndrome. If these are suspected on clinical
grounds, appropriate diagnostic and management pathways should be set in motion
right away. The recommendation in favor of this intervention is strong 38.

18
LIST OF ESSENTIAL MEDICINES FOR THE TREATMENT OF PATIENTS
ADMITTED TO INTENSIVE CARE UNITS WITH A SUSPECTED OR CONFIRMED
DIAGNOSIS OF COVID-19

MEDICINE DOSAGE FORM AND CONCENTRATION

DRUGS FOR FEVER

Paracetamol Injection: 10-ml ampoule with 10 mg/ml or vial containing 50-100
ml

MEDICINAL GASES
Oxygen Inhalation. For use in the management of hypoxemia

DRUGS FOR ANALGESIA

Fentanyl Injectable: 5-ml ampoule with 50 µg/ml
Morphine Injection: 1-ml ampoule with 10 mg (of sulfate or chlorhydrate)
DRUGS FOR SEDATION
Haloperidol Injection: 1-ml ampoule with 5 mg

Lorazepam Parenteral formulation: 1-ml ampoule with 2 mg/ml; 1-ml ampoule

with 4 mg/ml
Midazolam Injection: 1 mg/ml and 5 mg/ml
Propofol Injection: ampoule with 10 mg/ml, 20 mg/ml
MUSCLE RELAXANTS
Atracurium* Injection: ampoule with 10 mg/ml (besilate)
*Vecuronium powder for injection: 10 mg (bromide) in vial, as an option
depending on local availability
Succinylcholine Injection: 2-ml ampoule with 50 mg (chloride)/ml
ADJUVANTS FOR SEDATION
Atropine Injection: 1-ml ampoule with 1 mg (sulfate)

ANTIMICROBIALS
(Used to treat coinfections. See note regarding use in accordance with local
guidelines.)

Amikacin Injection: 2-ml vial with 250 mg (sulfate)/ml

Amoxicillin + Powder for injection: 500 mg (sodium) + 100 mg (as potassium
clavulanic acid* salt); 1000 mg (sodium) + 200 mg (as potassium salt) in vial.

*Ampicillin sulbactam 1.5 g (ampicillin 1 g, sulbactam 0.5 g);

3 g (ampicillin 2 g, sulbactam 1 g) as an alternative depending on local
availability
Amphotericin B Powder for injection: 50 mg in vial (as sodium deoxycholate or
liposomal complex)
Clarithromycin Powder for injection: 500 mg in vial
Ceftazidime Powder for injection: 250 mg or 1 g (as pentahydrate) in vial
Ceftriaxone Powder for injection: 250 mg; 500 mg; 1 g in vial

19
MEDICINE DOSAGE FORM AND CONCENTRATION

Meropenem* Powder for injection: 500 mg (as trihydrate); 1 g (as trihydrate) in

vial
*Optionally: imipenem + cilastatin 250 mg/250 mg, 500 mg/500 mg, as
alternatives depending on local availability
Piperacillin + Powder for injection: 2 g (as sodium salt) + 250 mg (as sodium
tazobactam salt); 4 g (as sodium salt) + 500 mg (as sodium salt) in vial
Vancomycin Powder for injection: 250 mg (as chlorhydrate) in vial
GLUCOCORTICOIDS
Hydrocortisone* Powder for injection: 100 mg (as sodium succinate) in vial

*Conditional.
For specific uses
detailed at the
bottom of the table
**Dexamethasone 1-ml ampoule with 4 mg/ml (as disodium phosphate)

**For specific uses

detailed at the
bottom of the table
VASOACTIVE DRUGS
Dobutamine Injection: 20-ml ampoule with 5, 10, 25, 50 and 100 mg (as
chlorhydrate)
Epinephrine* Injection: 1-ml ampoule with 1 mg (as chlorhydrate or tartrate).
(adrenaline) Injection: 10-ml ampoule with 100 µ/ml (as tartrate or
chlorhydrate)

First one in children

*Vasopressin solution for injection: 20 units/ml as alternative depending

on local availability
Norepinephrine* Injection: 4-ml ampoule with 1 mg/ml
(noradrenaline)
*As first choice
VOLUME EXPANDERS (CRYSTALLOIDS)
Ringer's lactate Ringer´s with sodium lactate, compound solution. Injectable
Normal saline Injectable solution: isotonic (0.9%) (equivalent to 154 mmol/L of
Na+ and 154 mmol/L of Cl-)
DRUGS FOR COINFECTION WITH INFLUENZA VIRUS
Oseltamivir* Capsule: 30 mg; 45 mg; 75 mg (as phosphate). Oral powder: 12
mg/ml
*Reserved for severe illness caused by suspected or confirmed
coinfection with influenza virus in critically ill hospitalized patients.
ANTICOAGULANTS
Enoxaparin Injection: ampoule or prefilled syringe with 20 mg/0.2 ml; 40
mg/0.4 ml; 60 mg/0.6 ml; 80 mg/0.8 ml; 100 mg/1 ml; 120 mg/0.8
ml; 150 mg/1 ml

*Alternatives are limited to nadroparin and dalteparin.

20
MEDICINE DOSAGE FORM AND CONCENTRATION

ANTACIDS
Omeprazole Powder for injection: 40 mg in vial
Ranitidine Injection: 2-ml ampoule with 25 mg/ml (as chlorhydrate)
ANTIEMETICS
Metoclopramide Injection: 2-ml ampoule with 5 mg (chlorhydrate)/ml
Ondansetron Injection: 2-ml ampoule with 2 mg/ml (as chlorhydrate)
ANTISEPTICS AND DISINFECTANTS
Alcohol for hands Solution: contains 75% isopropyl alcohol (isopropanol) or 80%
ethanol, volume/volume
Chlorhexidine Solution: 5% (digluconate)
Iodopovidone Solution: 10% (equivalent to 1% available iodine)
BRONCHODILATORS
Ipratropium bromide Inhalation (aerosol): 20 micrograms/dose

Salbutamol Inhalation (aerosol): 100 micrograms (sulfate) per dose

Injection: 5-ml ampoule with 50 micrograms (sulfate) per ml
• The drugs or presentations in italics are not part of the WHO Model List of Essential
Medicines but were included on the basis of the evidence and recommendations presented
herein.
• *Use of hydrocortisone limited to patients with: (a) respiratory failure and ARDS; (b) COVID-
19, in shock and before adding a second vasopressor; (c) COVID-19 and viral pneumonia,
only if experiencing exacerbation of asthma or chronic obstructive pulmonary disease
(COPD), septic shock or ARDS.
• **Dexamethasone: use with proof of efficacy only in critically ill patients with COVID-19 who
require supplementary oxygen or assisted ventilation.

21
References

1. Walhazzani W, Møller M, Arabi Y, Loeb M, Gong M, Fan E, et al. Surviving Sepsis Campaign:
guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-
19). Intensive Care Med 2020; 46:854–887. https://doi.org/10.1007/s00134-020-06022-5
2. Weiss SL, Peters MJ, Alhazzani W, Agus MSD, Flori HR, Inwald DP, et al. Surviving Sepsis
Campaign international guidelines f or the management of septic shock and sepsis-
associated organ dysfunction in children. Intensive Care Med 2020; 46 (Suppl 1): S10–S67.
https://doi.org/10.1007/s00134-019-05878-6.
3. WHO. Clinical management of severe acute respiratory inf ection (SARI) when COVID-19
disease is suspected: interim guidance V 1.2. 13 March 2020.
4. España, Ministerio de Salud. Manejo clínico de pacientes con enf ermedad por el nuevo
coronavirus (COVID-19). 3 March 2020.
5. CDC. Interim clinical guidance f or management of patients with conf irmed coronavirus
disease (COVID-19). 7 March 2020.
6. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease
2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese
Center f or Disease Control and Prevention. JAMA 2020 Feb 24, (Published online) doi:
10.1001/jama.2020.2648.
7. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill
patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective,
observational study. Lancet Respir Med 2020 Feb 21, (Published online) doi:
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30079-5/fulltext.
8. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized
patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA.
2020;323(11):1061-1069. doi: 10.1001/jama.2020.1585
9. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with
2019 novel coronavirus in Wuhan, China. Lancet 2020;395: 497-506. doi: 10.1016/S0140-
6736(20)30183-5
10. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of
adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020
March 11; doi: https://doi.org/10.1101/2020.08.12.20173302
11. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this
hemodynamically unstable patient respond to a bolus of intravenous f luids? JAMA. 2016;
316: 1298-1309. doi: 10.1001/jama.2016.12310
12. Meyhoff TS, Moller MH, Hjortrup PB, Cronhjort M, Perner A, Wetterslev J. Lower versus
higher f luid volumes during initial management of sepsis: a systematic review with
metaanalysis and trial sequential analysis. Chest 2020 Jan 23; doi:
https://doi.org/10.1016/j.chest.2019.11.050
13. Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, Blackwood B,
Fan E. Conservative f luid management or deresuscitation for patients with sepsis or acute
respiratory distress syndrome f ollowing the resuscitation phase of critical illness: a systematic
review and meta-analysis. Intensive Care Med 2017;43: 155-170 53. doi: 10.1007/s00134-
016-4573-3
14. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, Nyeko R, Mtove G,
Reyburn H, Lang T, Brent B, Evans JA, Tibenderana JK, Crawley J, Russell EC, Levin M,
Babiker AG, Gibb DM, Group FT. Mortality af ter f luid bolus in Af rican children with severe
inf ection. N Engl J Med 2011; 364: 2483-2495.

22
15. Antequera Martin AM, Barea Mendoza JA, Muriel A, Saez I, Chico-Fernandez M, Estrada
Lorenzo JM, Plana MN, Buffered solutions versus 0.9% saline for resuscitation in critically ill
adults and children. Cochrane Database Syst Rev 2019 7: CD012247.
16. Lewis SR, Pritchard MW, Evans DJ, Butler AR, Alderson P, Smith AF, Roberts I. Colloids
versus crystalloids for f luid resuscitation in critically ill people. Cochrane Database Syst Rev
2018 Rev 8: CD000567.
17. Gamper G, Havel C, Arrich J, Losert H, Pace NL, Mullner M, Herkner H, Vasopressors for
hypotensive shock. Cochrane Database Syst Rev 2: CD003709;2016.
18. Honarmand K, Um KJ, Belley-Cote EP, Alhazzani W, Farley C, Fernando SM, Fiest K, Grey
D, Hajdini E, Herridge M, Hrymak C, Moller MH, Kanji S, Lamontagne F, Lauzier F, Mehta S,
Paunovic B, Singal R, Tsang JL, Wynne C, Rochwerg B. Canadian Critical Care Society
clinical practice guideline: The use of vasopressin and vasopressin analogues in critically ill
adults with distributive shock. Can J Anaesth 2020; 67: 369-376.
19. McIntyre WF, Um KJ, Alhazzani W, Lengyel AP, Hajjar L, Gordon AC, Lamontagne F, Healey
JS, Whitlock RP, Belley-Cote EP. Association of vasopressin plus catecholamine
vasopressors vs catecholamines alone with atrial fibrillation in patients with distributive shock:
A systematic review and meta-analysis. JAMA. 2018;319: 1889-1900.
20. Moller MH, Granholm A, Junttila E, Haney M, Oscarsson-Tibblin A, Haavind A, et al.
Scandinavian SSAI clinical practice guideline on choice of inotropic agent for patients with
acute circulatory failure. Acta Anaesthesiol Scand 2018; 62: 420-450.
21. Rygard SL, Butler E, Granholm A, Moller MH, Cohen J, Finf er S, et al. Low-dose
corticosteroids for adult patients with septic shock: a systematic review with meta-analysis
and trial sequential analysis. Intensive Care Med 2018; 44: 1003-1016.
22. Lamontagne F, Rochwerg B, Lytvyn L, Guyatt GH, Moller MH, Annane D, et al. Corticosteroid
therapy f or sepsis: a clinical practice guideline. BMJ 2018; 362: k3284.
23. Lewis SR, Pritchard MW, Thomas CM, Smith AF. Pharmacological agents f or adults with
acute respiratory distress syndrome. Cochrane Database Syst Rev 2019, Issue 7. Art. No.:
CD004477. doi:
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004477.pub3/full
24. Ni Y-N, Chen G, Sun J, Liang B-M, Liang Z-A. The ef f ect of corticosteroids on mortality of
patients with inf luenza pneumonia: a systematic review and meta-analysis. Critical Care
2019; 23: 99.
25. Huang C, Wang Y, Li Y, et al. Clinical f eatures of patients inf ected with 2019 novel
coronavirus in Wuhan, China. Lancet 2020; 395: 497–506.
26. Rhodes A, Evans L, Alhazzani W, Levy M, Antonelli M, Ferr R, et al. Surviving Sepsis
Campaign: international guidelines f or management of sepsis and septic shock: 2016.
Intensive Care Med 2017; 43:304–377er6
27. Sinha I. Guidance f or the clinical management of children admitted to hospital with proven
COVID-19. Alder Hey Children’s Hospital: clinical management of children admitted to
hospital with covid-19 (covid-19). version 1. March 2020.
28. Barton GJ, Morecroft CW, Henney NC. A survey of antibiotic administration practices
involving patients with sepsis in UK critical care units. Int J Clin Pharm 2019;
https://doi.org/10.1007/s11096-019-00938-9.
29. Jacobi J, Fraser GL, Coursin DB et al. Practice guidelines for the sustained use of sedatives
and analgesics in the critically ill adult. Crit Care Med. 2002; 30:119-141.
30. Barr j, Gilles LF et al. Clinical practice Gguidelines for the management of pain, agitation, and
delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263–306.

23
31. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines f or the prevention and
management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult
patients in the ICU. Crit Care Med 2018; 46: e825–e873.
32. Murray MJ, DeBlock H, Erstad B, et al. Clinical practice guidelines f or sustained
neuromuscular blockade in the adult critically ill patient. Crit Care Med 2016; 44:2079–2103.
33. Papazian L, Forel JM, Gacouin A et al. Neuromuscular blockers in early acute respiratory
distress syndrome. N Engl J Med 2010; 363:1107-16.
34. Miller’s Anesthesia. Chapter 34: Pharmacology of neuromuscular blocking drugs. Saunders
Eighth Edition; 2015.
35. Lavery GG, McCloskey BV. The difficult airway in adult critical care. Crit Care Med. 2008; 36:
2163-73.
36. Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, et al. Dexamethasone
treatment f or the acute respiratory distress syndrome: a multicentre, randomised controlled
trial. Lancet Respir Med. 2020 Mar;8(3):267-276.
37. Broersen LH, Pereira AM, Jørgensen JO, et al. Adrenal insufficiency in corticosteroids use:
systematic review and meta-analysis. J Clin Endocrinol Metab. 2015; 100:2171–2180.
38. WHO. Clinical management of COVID-19. Interim guidance. 27 May 2020.
39. Hammond DA, Lam SW, Rech MA, et al. Balanced crystalloids versus saline in critically Ill
adults: a systematic review and meta-analysis. Ann Pharmacother. 2020;54(1):5‐13. doi:
10.1177/1060028019866420
40. Andrews B, Semler MW, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, et al. Effect of an
early resuscitation protocol on in-hospital mortality among adults with sepsis and
hypotension: a randomized clinical trial. JAMA. 2017;318(13):1233-40.
41. Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-
CoV-2 inf ection. Clin Chem Lab Med 2020. https://www.ncbi.nlm.nih.gov/pubmed/32172226.
42. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health
care workers, and health systems during the coronavirus disease 2019 (COVID-19)
pandemic. J Am Coll Cardiol 2020.
43. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment
Guidelines. National Institutes of Health. Available at:
https://www.covid19treatmentguidelines.nih.gov
44. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N
Engl J Med. 2020. https://www.ncbi.nlm.nih.gov/pubmed/32109013
45. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with
decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J
Thromb Haemost. 2020;18(5):1094-1099.
46. Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in
anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020. pubmed/32320517.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264774/
47. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-
CoV-2 inf ection: a multicenter prospective cohort study. Intensive Care Med 2020:[Preprint].
https://www.esicm.org/wpcontent/uploads/2020/04/863_author_proof.pdf
48. Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in critically
ill ICU patients with COVID-19. Thromb Res. 2020.
https://www.ncbi.nlm.nih.gov/pubmed/32291094
49. Rawson TM, Moore LSP, Zhu N, Ranganathan N, Skolimowska K, Gilchrist M, et al. Bacterial
and f ungal co-infection in individuals with coronavirus: a rapid review to support COVID-19
antimicrobial prescribing. Clin Inf ect Dis. 2020. Epub 2020/05/03.

24
50. WHO. World Health Organization Model List of Essential Medicines. 21st List 2019.
51. WHO. Clinical care f or severe acute respiratory inf ection: toolkit. COVID-19 adaptation.
Geneva: 2020 (WHO/2019nCoV/SARI_toolkit/2020.1).
52. Wanga R, Pana M, Zhanga X et al. Epidemiological and clinical features of 125 Hospitalized
Patients with COVID-19 in Fuyang, Anhui, China. Int J Inf ect Dis (2020) 421–428.
53. WHO. The selection and use of essential medicines: report of the WHO Expert Committee,
2017 (including the 20th WHO Model List of Essential Medicines and the 6th Model List of
Essential Medicines for Children).
54. Pakhale S, Mulpuru S, Verheij TJ, Kochen MM, Rohde GG, Bjerre LM. Antibiotics for
community-acquired pneumonia in adult outpatients. Cochrane Database Syst Rev. 2014;
2014(10):CD002109.
55. FDA Drug Saf ety Communication: Azithromycin (Zithromax or Zmax) and the risk of
potentially fatal heart rhythms. 2013.
56. FDA Drug Safety Communication. FDA review finds additional data supports the potential for
increased long-term risks with antibiotic clarithromycin (Biaxin) in patients with heart disease.
2018.
57. Winkel P, Hilden J, Fischer Hansen J, et al, Clarithromycin for stable coronary heart disease
increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10
years in the CLARICOR randomised, blinded clinical trial. Int J Cardiol 2015; 182:459-465.
58. Jespersen CM, Als-Nielsen B, Damgaard M, et al. Randomised placebo controlled
multicenter trial to assess short term clarithromycin f or patients with stable coronary heart
disease: CLARICOR trial. BMJ 2006; 332:22-7.
59. NICE. Pneumonia (community acquired): antimicrobial prescribing. 16 September 2019.
60. NHS. Clinical guide for the management of critical care for adults with COVID-19 during the
coronavirus pandemic. 8 April 2020, version 2.
61. PAHO. Guidelines for care of critically ill adult patients with COVID-19 in the
Americas: short version – v2. Updated to July 29, 2020
62. Mercuro NJ, Yen CF, Shim DJ, Maher TR, McCoy CM, Zimetbaum PJ, et al. Risk of QT
interval prolongation associated with use of hydroxychloroquine with or without concomitant
azithromycin among hospitalized patients testing positive f or coronavirus disease 2019
(COVID-19). JAMA Cardiol. 2020 May 1:e201834. doi: 10.1001/jamacardio.2020.1834
63. Chorin E, Dai M, Shulman E, Wadhwani L, Cohen R, Barbhaiya C, et al. The QT interval in
patients with SARS-CoV-2 infection treated with hydroxychloroquine/azithromycin. Published
online 2 April 2020. https://www.medrxiv.org/content/10.1101/2020.04.02.20047050v1
64. NICE. COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital. 1 May 2020
65. Phua J, Weng L, Ling L, Egi M, Lim C, Divatia J, et al. Intensive care management of
coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Respir
Med 2020; 8: 506–17. 6 April 2020
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30161-2/fulltext
66. Murthy S, Gomersall C, Fowler R. Care for Critically Ill Patients With COVID-19. JAMA 2020;
323 (15): 1499-1500.
67. Mammen MJ, Aryal K, Alhazzani, W et al. Corticosteroids for patients with acute respiratory
distress syndrome: a systematic review and meta-analysis of randomized trials. Pol Arch
Intern Med. 2020 Apr 30;130(4):276-286. doi: 10.20452/pamw.15239.
68. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with
severe respiratory complications of COVID-19. 16 June 2020.
https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-
third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19

25
69. Horby P, Shen Lim W, Emberson J, Maf ham M, Bell J, Linsell L, et al. Effect of
dexamethasone in hospitalized patients with COVID-19: preliminary Report. doi:
https://doi.org/10.1101/2020.06.22.20137273.
https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1
70. WHO. WHO welcomes preliminary results about dexamethasone use in treating critically ill
COVID-19 patients. 16 June 2020. https://www.who.int/news-room/detail/16-06-2020-who-
welcomes-preliminary-results-about-dexamethasone-use-in-treating-critically-ill-covid-19-
patients
71. Jeong H, Lee H, Shin H, Choe Y, Filion K, Shin JY. Association between NSAIDs use and
adverse clinical outcomes among adults hospitalised with COVID-19 in South Korea: a
nationwide study. Clin Infect Dis 2020; ciaa1056. doi: 10.1093/cid/ciaa1056. Online ahead
of print.
72. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for
the treatment of Covid-19 - Preliminary Report. N Engl J Med 2020 May 22:
NEJMoa2007764. doi: 10.1056/NEJMoa2007764.
73. Dorati C, Mordujovich Buschiazzo P, Marin G, Buschiazzo H. Remdesivir para el tratamiento
de inf ección por COVID-19. Report of a rapid review. 18 May 2020. CUFAR. Centro
Universitario de Farmacología. Centro Colaborador OPS/OMS en el uso racional de
medicamentos. Facultad de Ciencias Médicas. Universidad Nacional de La Plata. Argentina.
https://sites.bvsalud.org/redetsa/brisa/resource/?id=biblioref.referencesource.1096930
74. PAHO. Ongoing living update of potential COVID-19 therapeutics: summary of rapid
systematic reviews. Rapid Review – 13 July 2020.
75. Rawson TM, Moore LSP, Zhu N, Ranganathan N, Skolimowska K, Gilchrist M, et al. Bacterial
and f ungal co-infection in individuals with coronavirus: a rapid review to support COVID-19
antimicrobial prescribing. Clin Inf ect Dis. 2020. Epub 2020/05/03
76. Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, et al. Tocilizumab in
patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. Published:
24 June 2020. doi: https://doi.org/10.1016/S2665-9913(20)30173-9.
77. Tocilizumab improves significantly clinical outcomes of patients with moderate or severe
COVID-19 pneumonia. 2020. Available at:
https://pipelinereview.com/index.php/2020042874458/Antibodies/Tocilizumab-improves-
significantly-clinical-outcomes-of-patients-with-moderate-or-severe-COVID-19-
pneumonia.html
78. WHO. “Solidarity” clinical trial for COVID-19 treatments. Available at:
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-
novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
79. Recovery Trial. No clinical benefit f rom use of hydroxychloroquine in hospitalised patients
with COVID-19. 5 June 2020. Available at: https://www.recoverytrial.net/news/statement-
f rom-the-chief-investigators-of-the-randomised-evaluation-of -covid-19-therapy-recovery-
trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-
hydroxychloroquine-in-hospitalised-patients-with-covid-19
80. Recovery Trial. No clinical benefit f rom use of lopinavir-ritonavir in hospitalised COVID-19
patients studied in Recovery. 29 June 2020. Available at:
https://www.recoverytrial.net/news/no-clinical-benefit-from-use-of-lopinavir-ritonavir-in-
hospitalised-covid-19-patients-studied-in-recovery
81. WHO. International Clinical Trials Registry Portal (ICTRP). https://apps.who.int/trialsearch/
82. Ye Z, Wang Y, Colunga-Lozano LE, et al. Efficacy and safety of corticosteroids in COVID-19
based on evidence f or COVID-19, other coronavirus inf ections, inf luenza, community

26
 acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-
analysis. CMAJ. 2020;192(27):E756-E767. doi: 10.1503/cmaj.200645
83. Lu S, Zhou Q, Huang L, Shi Q, Zhao S, Wang Z, Li W, Tang Y, Ma Y, Luo X, Fukuoka T, Ahn
HS, Lee MS, Luo Z, Liu E, Chen Y, Zhou C, Peng D. Ef fectiveness and saf ety of
glucocorticoids to treat COVID-19: a rapid review and meta-analysis. Ann Transl Med. 2020
May;8(10):627.
84. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in
hospitalized patients with Covid-19: preliminary report. N Engl J Med 2020 Jul 17. doi:
10.1056/NEJMoa2021436
85. Horby P, Maf ham M, Linsell L, Bell J, Staplin N, Emberson J, et al. Ef fect of
hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-
centre, randomized, controlled trial. 15 July 2020. doi:
https://doi.org/10.1101/2020.07.15.20151852

The Pan American Health Organization (PAHO) is grateful for the technical support provided by Pearl
Mordujovich-Buschiazzo, Cristian M. Dorati, Gustavo H. Marín, Guillermo R. Prozzi, and Héctor O.
Buchiazzo. CUFAR. University Center f or Pharmacology. PAHO/WHO Collaborating Centre for
Rational Use of Medicines. School of Medicine. National University of La Plata (Argentina).

The authors have no conflict of interests to declare.

Date of the first edition: 24 March 2020. Updated: 10 August 2020.

This document was prepared with support f rom the European Union through the “Working together
to f ight antimicrobial resistance” project. The opinions expressed in this document in no way represent
the of ficial views of the European Union.

PAHO/IMS/HSS/COVID-19/20-0031

© Pan American Health Organization, 2020. Some rights reserved. This work is available
under license CC BY-NC-SA 3.0 IGO.

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